What We Know About Gene Therapy And How Can It Be Used For Heart Failure

After the flop in an important study two years ago, interest in gene therapy for the heart is growing again. A single injection could be enough to cure the problem.

For more than a decade, scientists have been trying to treat heart failure by providing the heart with a new gene to improve its ability to pump and oxygenate the body.

Renewed interest in gene therapy

A large clinical trial in 2015, in which such a therapy was to be tested, was a flop. But now that gene therapies have become a reality after years of preliminary work on other diseases, interest in their use against heart failure is growing again.

A team at the Icahn School of Medicine in New York, led by Roger Hajjar, recently tested such a therapy on pigs and the results were encouraging. Hajjar was one of the co-founders of the biotech company Celladon, which financed the failed study.

In the new study, 6 of 13 pigs with severe heart failure received gene therapy, the remaining 7 received a saline solution as placebo. Gene therapy proved to be safe and reduced heart failure in the left ventricle by 25 percent and in the left atrium by 20 percent. According to Hajjar, most heart failure patients have problems with the left ventricle. In addition, the enlarged hearts of the pigs were reduced by 10 percent as a result of the therapy.

Preparations for clinical tests

For Hajjar, pigs are good test objects for such therapies because their hearts are about as big as those of humans. Next year, he plans to start recruiting people with advanced congestive heart failure to participate in a clinical trial.

In heart failure, the heart does not simply stop beating. But it is difficult to pump enough blood through the body. It tries to balance this by growing and beating faster, but eventually it stops coming along. The consequences are fatigue and difficulty breathing.

Protein as a starting point for gene therapy

Hajjar’s new therapy uses a gene that regulates a protein called phosphatase-1. It is more abundant in people with heart failure, and too much of it reduces the heart’s ability to contract. Hajjar therefore considers this protein to be a suitable starting point for improving the pumpability of damaged hearts.

This approach differs from traditional gene therapies for inherited diseases that aim to correct a single gene mutation. Hajjar, on the other hand, targets a common consequence of a disease. “By identifying molecular targets found in all patients with heart failure, we could treat all patients instead of just those with specific gene mutations,” he explains.

The gene is packaged in an artificial virus that reaches the heart cells. The therapy would be injected via the radial or femoral artery, the largest in the human body.

More effective transport to the heart

According to Hajjar, he and his colleagues learned from the failure of Celladon gene therapy. At the time, they had tried to improve muscle contraction in the heart by restoring a protein missing from damaged hearts. However, in tests with 250 patients in more than 50 centers in the US and Europe, the therapy showed no significant effect.

Hajjar believes that the problem was that the therapy did not reach enough heart muscle cells. For the current experiment, Hajjar and his colleagues have redesigned the viral vector so that it transports the new gene more effectively to the heart.

Walter Koch, president for cardiovascular medicine and head of the Center for Translational Medicine at Temple University, describes Hajjar’s study as promising. However, the transport of the virus to the heart is not the only challenge – it also has to be “transported into enough cells”. Koch has been working on a gene therapy for heart failure for more than a decade. The aim is to cure the disease with a single injection. “We believe that only once will be enough,” he says.

Cure for heart failure?

For Koch, medicine is closer to a genetic cure for heart failure than ever before, especially now that Big Pharma is also investing in the idea – ten years ago, things were different. Pfizer, for example, concluded a cooperation agreement last year with 4D Molecular Therapeutics from California on the development of viral vectors for heart diseases.

The Dutch company UniQure, manufacturer of the first gene therapy in the western world, is also working on a therapy for heart failure. Bristol-Myers Squibb has entered into a partnership with him in 2015 to develop the drug to market maturity. Upon request, UniQure announced that its gene therapy had so far been mainly tested on miniature pigs. The company did not provide any information about the start of possible clinical studies.